Prostate cancer is a leading cause of morbidity and mortality among men. Treatments for prostate cancer include surgery, hormones, radiation, and chemotherapy. There is little effective treatment for metastatic prostate disease. Therefore, the identification of genes and/or gene products that represent diagnostic and prognostic markers, as well as targets for therapy, is critical. Prostate specific antigen (PSA) is one such cancer marker which is useful in the clinical diagnosis and staging of prostate cancer. However, PSA cannot differentiate benign prostatic hyperplasia (BPH) from prostatitis or prostate cancer in the range of 4-10 ng/ml, thus, necessitating a cytologic and/or histologic assessment to confirm the proper diagnosis (Barren, R. J. et al. (1998) Prostate 36:181-188).
Prostate specific membrane antigen (PSMA) is a 750 amino acid, type II transmembrane glycoprotein of approximately 110 kD that has 54% homology to the transferrin receptor. PSMA has 3 structural domains, including a 19 amino acid intracellular domain, a 24 amino acid transmembrane domain, and a 707 amino acid extracellular domain. The PSMA protein displays neurocarboxypeptidase and folate hydrolase activity and is reported to be involved in the neuroendocrine regulation of prostate growth and differentiation (Heston, W. D. (1996) Urologe-Ausgabe A. 35:400-407). PSM′ is an alternatively spliced form of PSMA which is localized in the cytoplasm.
PSMA is predominantly expressed by prostatic epithelial cells. The expression of PSMA is increased in prostate cancer, especially in poorly differentiated, metastatic, and hormone refractory carcinomas (Gregorakis, A. K. et al. (1998) Seminars in Urologic Oncology 16:2-12; Silver, D. A. (1997) Clinical Cancer Research 3:81-85). Low level expression of PSMA is observed in extraprostatic tissues such as the small bowel, salivary gland, duodenal mucosa, proximal renal tubules, and brain (Silver, D. A. (1997) Clinical Cancer Research 3:81-85). PSMA is also expressed in endothelial cells of capillary vessels in peritumoral and endotumoral areas of certain malignancies, including renal cell carcinomas, and colon carcinomas, but not in blood vessels from normal tissues. In addition, PSMA is reported to be related to tumor angiogenesis (Silver, D. A. (1997) Clinical Cancer Research 3:81-85).
Antibodies against the extracellular domain of PSMA have been described (see e.g., Liu, H. et al (1997) Cancer Res. 57:3629-3634; Murphy, G. P. et al. (1998) J. Urol. 160:2396-2401; Wang, S. et al. (2001) Int. J. Cancer 92:871-876; Kato, K. et al. (2003) Int. J. Urol. 10:439-444; U.S. Pat. No. 6,150,508 and U.S. Pat. No. 6,107,090). More recently, human and humanized antibodies that bind PSMA have been described (see e.g., Bander, N. H. et al. (2003) Semin. Oncol. 30:667-676; PCT Publication WO 02/098897; PCT Publication WO 01/09192; PCT Publication WO 03/064606; PCT Publication WO 03/034903; and US Application No. 2004/0033229). Such antibodies have been used for imaging of prostate cancer cells (see e.g., Yao, D. et al. (2002) Semin. Urol. Oncol. 20:211-218; Bander, N. H. et al. (2003) J. Urol. 170:1717-1721). Anti-PSMA antibodies also have been used for therapeutic intervention in treatment of prostate cancer, typically as a conjugate with a chemotherapeutic agent or radioactive isotope (see e.g., Nanus, D. M. et al. (2003) J. Urol. 170:S84-89; Milowsky, M. I. et al. (2004) J. Clin. Oncol. 22:2522-2531; Henry, M. D. et al. (2004) Cancer Res. 64:7995-8001).
Improved therapeutic antibodies against PSMA that are effective for treating and/or preventing diseases involving PSMA expression, particularly antibodies that have cytotoxic effects without the need to be conjugated to a chemotherapeutic agent or radioactive isotope, are desired.